Method and partitioning blood using polyesters

ABSTRACT

A polyester is provided which facilitates the separation of blood into light and heavy phases via centrifugation in a blood collection vessel. The polyester is useful as a component of a partitioning composition formulated to have appropriate specific gravity to be positioned intermediate the light and heavy blood phases during centrifugation. The polyester composition can be prepared with relative ease compared to prior art polyesters useful in blood partitioning compositions. The polyesters of this invention comprise a dicarboxylic acid member, a polymeric fatty acid, a diol member and a moiety having at least one polymerizable carbon-carbon double bond and at least one functional group capable of reacting with the ends of the polyester chain. The polyesters have a lower viscosity when synthesized and are later cured to increase their viscosity to the desired level.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to polyesters useful forfacilitating the separation of blood serum or plasma from the cellularportion of blood.

[0003] 2. Description of the Related Art

[0004] The compositions of the present invention are convenientlyformulated into a partitioning composition for use in a blood collectionvessel in which the blood sample is subjected to centrifugation untilthe cellular portion and serum or plasma are completely separated.

[0005] Note that while blood is the most usual candidate forphysiological separation, conceivably urine, milk, sputum, stoolsolutions, meconium, pus and the like could all be subject tophysiological separation and assay for therapeutic agents and thesubsequent discussion, while focusing on blood for clarity, is not meantto be limited to blood.

[0006] The physical and chemical properties of the partitioningcomposition are such that a continuous, integral seal is providedbetween the separated blood phases, thereby maintaining separation ofthe phases after centrifugation and simplifying removal of the serum orplasma from the blood collection vessel. The high volume testing ofblood components in hospitals and clinics has led to the development ofvarious devices to simplify the collection of blood samples andpreparation of the samples for analysis. Typically, whole blood iscollected in an evacuated, elongated glass tube that is permanentlyclosed at one end and sealed at the other end by a rubber stopper havinga diaphragm which is penetrated by the double-tipped cannula used todraw the patient's blood. After the desired quantity of blood iscollected, the collection vessel is subjected to centrifugation to yieldtwo distinct phases comprising the cellular portion of the blood (heavyphase) and the blood serum or plasma (light phase). The light phase istypically removed from the collection vessel, e.g., via pipette ordecantation, for testing.

[0007] It has been proposed heretofore to provide manufactured,seal-forming members, e.g., resilient pistons, spools, discs and thelike, in blood collection vessels to serve as mechanical barriersbetween the two separated phases. Because of the high cost ofmanufacturing such devices to the close tolerances required to provide afunctional seal, they have been supplanted by fluid sealantcompositions. Fluid sealant compositions are formulated to have aspecific gravity intermediate that of the two blood phases sought to beseparated, so as to provide a partition at the interface between thecellular and serum phases. Such compositions typically include a polymerbase material, one or more additives for adjusting the specific gravityand viscosity of the resultant composition, and optionally, a networkformer. Representative fluid sealant compositions developed in the pastinclude: styrene beads coated with an anti-coagulant; silicone fluidhaving silica dispersed therein; a homogeneous, hydrophobic polyesterincluding a suitable filler, e.g., silica; a liquidalpha-olefin-dialkylmaleate, together with an aliphatic amine derivativeof smectite clay or powdered silica; the reaction product of a siliconefluid with a silica filler and a network former; and a mixture ofcompatible viscous liquids, e.g., epoxidized vegetable oil andchlorinated polybutene, and a thixotropy-imparting agent, e.g., powderedsilica, and liquid polyesters, a thixotropic gel comprising a dual resincomponent including poly-alpha-pinene of lower density combined withchlorinated octadecene of higher density, said gel further comprising aradiation stabilizer, a network stabilizer, a thixotropic agent and apigment, and a gelatinous material admixed with fine resin particleshaving an average particle size of 0.01 to 2 microns and having aninternal crosslinking density of 0.1 to 3 mmol/g.

[0008] Ideally, a commercially useful blood partitioning compositionshould maintain uniform physical and chemical properties for extendedtime periods prior to use, as well as during transportation andprocessing of blood samples, readily form a stable partition undernormal centrifugation conditions and be relatively inert or unreactivetoward the substance(s) in the blood whose presence or concentration isto be determined.

[0009] Inertness to substances sought to be determined is a particularconcern when blood collection vessels are used for therapeutic drugmonitoring (TDM), which is assuming an increasingly important role indrug treatment strategies. TDM enables the administration of drugs inthe appropriate therapeutic ranges, established through the accumulatedexperience of clinicians, and consequently reduces the number ofpatients receiving dosage levels that are either below detection limitsor toxic. Administration of drugs under TDM allows one to take intoaccount such factors as drug tolerance developed with passage of time,presence of multiple physical disorders and synergistic or antagonisticinteractions with other therapeutic agents. Among the drugs recommendedfor administration under TDM are those having dangerous toxicity withpoorly defined clinical endpoint, steep dose-response curve, narrowtherapeutic range, considerable inter-individual pharmacokineticvariability or non-linear pharmacokinetics, as well as those used inlong term therapy or in the treatment of life-threatening diseases. Byway of example, the evaluation of blood levels of a number of tricyclicantidepressant compounds, such as imipramine or desipramine, in relationto an empirically established therapeutic range is reported to beparticularly useful in the treatment of seemingly drug-refractivedepression. TDM is likewise used to monitor the dosage of anticonvulsantdrugs, such as phenytoin and phenobarbital which are administered in thetreatment of epilepsy, anti-tumor drugs, such as methotrexate, and othermore commonly prescribed drugs, including, but not limited to digoxin,lidocaine, pentobarbital and theophylline.

[0010] Reports of studies on the effect of blood partitioningcompositions on drug concentrations in serum and plasma indicate thatcare must be taken in the selection of polymeric materials which comeinto contact with the blood samples obtained for drug assay. See, forexample, P. Orsulak et al., Therapeutic Drug Monitoring, 6:44448 (1984)and Y. Bergquist et al. Clin. Chem., 30:465-6 (1984). The results ofthese studies show that the blood partitioning compositions provided inblood collection vessels may account for reduced serum or plasma values,as a result of drug absorption by one or more components of thecomposition. The reported decreases in measured drug concentrationsappears to be time dependent. One report concludes that the observeddecreases in drug concentrations may effectively be reduced byminimizing the interval between collection and processing. Anotherreport recommends that blood samples be transported to the laboratory assoon as possible, with processing occurring within 4 hours. Acommercially useful blood collection vessel, however, must produceaccurate test results, taking into account routine clinical practices inlarge institutions, where collection, transportation and processing ofblood samples may realistically take anywhere from about 1-72 hours.

[0011] Conventional polyester fluids are inadequate penetration barriersand therapeutic agents will diffuse into them and be partially absorbedwith time, which interferes with quantitative assay for their presence.Attempts to solve this problem have centered around techniques formaking the polyester itself more hydrophobic. Most therapeutic agentshave high solubility parameters and associated high hydrophilicity(associated with high polarity functional groups like amines) becausethey must be soluble in aqueous liquids like blood, and water has a highsolubility parameter. So, the direction has been to less hydrophilic,more hydrophobic, polymers to avoid the possibility of the therapeuticagents partially dissolving in a medium solubility parameter, mediumpolarity, polyester, and thus be more fully available in the serum phasefor analysis. Imparting hydrophobic character to the polyester has beendone via two main techniques. Firstly, a random polymer has been made ofa diol and large quantities of a dicarboxylic acid with pendent, long(C₉ to C₁₃) olefin groups. Secondly, a random polymer has been made of adiol and large quantities of a dicarboxylic with a long olefin along itsbackbone, such as a C₃₆ dimerized fatty acid. Such polyestercompositions have proved useful as functional blood partitioningcompositions having reduced affinity for therapeutic agents present inblood such as phenobarbital and imipramine. See, for example, W. L.O'Brien, U.S. Pat. No. 5,124,434, the entire disclosure of which isincorporated by reference in the present specification, as if set forthherein in full.

[0012] However many of these polyesters are highly viscous and difficultto transfer to the sample collection vials. It is therefore desirable tohave a material that will facilitate physiological separations but doesnot have the difficulties associated with transferring highly viscousliquids.

SUMMARY OF THE INVENTION

[0013] We have now quite unexpectedly discovered novel high molecularweight polyester compositions which are useful in blood separation tubesand which are derived from a short-chain dibasic acid, a polymeric fattyacid, a branched-chain saturated aliphatic diol or a mixture of diolshaving a branched-chain diol as the principal component and a moietyhaving at least one polymerizable carbon-carbon double bond and at leastone functional group capable of reacting with the ends of the polyesterchain. These polyester compositions are advantageously employed in smallamounts in blood separation tubes and form a tight seal between thelight and heavy phases of the blood. The polyester compositions are notaffected by contact with the blood and they do not alter the bloodcomponents. The polyesters of the invention can be synthesized havingone viscosity and then later be further polymerized or cured to increasetheir viscosity to a desired level. The density of the polymers is suchthat during the blood separation ultracentrifugation procedure theylocate at the interface between the serum or plasma phase and heaviercellular phase. When centrifugation is terminated the polymers form acontinuous integral barrier within the assembly to prevent the phasesfrom recombining or mixing especially when decanting or pipetting thelight phase. A small but effective amount, generally 2 to 5 grams, ofthe polyester sufficient to form the barrier between the phases isinserted directly into the separation tube either before or after theblood sample is collected. The polyester is in the form of a liquidhaving a density at room temperature in the range of about 1.01 to about1.09.

[0014] More particularly, the polyesters of the invention comprise asrepeating units:

[0015] A=(—C:O—R—O:C—) wherein A is the residue of a polymeric fattyacid, particularly preferred is the residue of C₃₆ dimer acid andwherein R_(A) is an aliphatic or aromatic moiety having from about 20 toabout 50 carbon atoms, preferably from about 22 to about 42 carbonatoms;

[0016] B=(—C:O—R_(B)—O:C—) wherein R_(B) is a member selected from thegroup consisting of a divalent aliphatic chain of 1-46 carbon atoms,preferably of from 1-34 and more preferably of from 3 to 34 carbonatoms; a divalent cycloaliphatic chain of 3-34 carbon atoms; a divalentarylene chain of from 6-34 carbon atoms, preferably of from 9-34; adivalent alkarylene chain of from 7-34 carbon atoms, a divalentalkarylalkylene chain of from 8-34 carbon atoms and mixtures thereof;

[0017] C=(—O—R_(C)—O—) wherein R_(C) is a member selected from the groupconsisting of compounds of the formula: R_(C)=(CH_(n) R_(m))_(k) whereinn=0, 1,2, or 3; R=H, C₁ to C₁₀ alkyl, CH₂OCH₂CH₂, CH₂CH₂OCH₂CH₂O CH₂CH₂;m=0, 1, or 2; n+m=2; k=1 to 10; examples of the (—O—R_(C)—O—) memberinclude, but are not limited to, 1,2 propylene glycol, 1,3 and 1,4butanediol, 3-methyl 1,5 penanediol, diethylene glycol, triethyleneglycol and the like; and

[0018] D=the residue of a compound having at least one polymerizablecarbon-carbon double bond and at least one functional group capable ofreacting with the ends of the polyester chain.

[0019] The polyesters are broadly characterized as being inert,hydrophobic, homogeneous compositions having molecular weights of fromabout 1,000 to 5,000 before curing, and can achieve molecular weights offrom about 5000 to 500,000 after curing, densities in the range of fromabout 1.015 to about 1.060 g/cm3 and 100 deg. C. viscosities (kinematic)in the range of from about 100 to about 1000 centistokes before curing,which after curing can be increased to about 500 to greater than 10,000centistrokes. Preferably, these polyesters will have 100 degree C.viscosities (kinematic) in the range of from about 100 to about 1000centistokes before curing, which can be increased by curing to about3,000 to about 6,000 centistrokes, and a density between of about 1.020to about 1.050 g/cm3. The molar ratio of the sum of R_(A) and R_(B) toR_(C) is in the range from about 1:1.5 to about 1:0.67.

[0020] The polyesters of this invention comprise a polymeric fatty acid(the repeating unit A), a dicarboxylic acid member (the repeating unitB), a diol member (the repeating unit C) and a moiety (the D component)having at least one polymerizable carbon-carbon double bond and at leastone functional group capable of reacting with the ends of the polyesterchain. Especially useful polyesters are derived from polymeric fattyacids having 70% by weight or more C₃₆ dimer acid, adipic, azelaic orsebacic acids, neopentyl glycol or a mixture of neopentyl glycol and1,2-propanediol and acrylic or methacrylic acid.

[0021] The polyesters of the present invention can be used as afunctional blood partitioning composition and can optionally beformulated together with other ingredients such as suitable filler andcompatible surfactant.

[0022] The polyesters of the invention can be formulated together withother ingredients, typically a suitable filler and compatiblesurfactant, into functional blood partitioning compositions. The densityof the finished blood partitioning composition is controlled withinprescribed limits, so that during centrifugation the composition becomesstably positioned at the interface between the serum or plasma phase andheavier cellular phase and, when centrifugation is terminated, forms acontinuous integral barrier within the blood collection vessel toprevent the two phases from recombining or mixing, especially whendecanting or pipetting the serum or plasma. The polyester bloodpartitioning composition can be transferred into the blood collectionvessel and cured, preferably by radiation, to increase the viscosity ofthe polyester composition to the desired level. The polyester-basedblood partitioning compositions of the invention are suited for use inTDM procedures.

DETAILED DESCRIPTION OF THE INVENTION

[0023] Other than in the operating examples, or where otherwiseindicated, all numbers expressing quantities of ingredients or reactionconditions used herein are to be understood as modified in all instancesby the term “about”. Practice within the numerical limits stated isgenerally preferred. Also, throughout this description, unless expresslystated to the contrary: percent, “parts” of, and ratio values are byweight; the description of a group or class of materials as suitable orpreferred for a given purpose in connection with the invention impliesthat mixtures of any two or more of the members of the group or classare equally suitable or preferred; description of constituents inchemical terms refers to the constituents at the time of addition to anycombination specified in the description or of generation in situ bychemical reactions specified in the description, and does notnecessarily preclude other chemical interactions among the constituentsof a mixture once mixed.

[0024] The polyesters according to the invention having the repeatingunits as set forth above, have molecular weights from about 1,000 toabout 5,000 before curing, and can achieve molecular weights from about5000 to 500,000 after curing. The polyesters of the invention areproduced in the form of liquids, having a density at room temperature inthe range of from about 1.01 to about 1.09. The inertness of thesepolyesters makes them useful in TDM programs. The polyesters of theinvention are also highly hydrophobic, exhibiting negligible watersolubility. The physical and chemical properties of these polyesters areuniformly maintained over extended periods prior to use, as well asduring transportation and processing of blood samples. These polyestershave the ability to undergo the ultracentrifugation necessary for theblood partitioning procedure without any detectable adverse effect.

[0025] The compositions of this invention have 100 degree C. viscosities(kinematic) in the range of from about 100 to about 1000 centistokesbefore curing, which after curing can be increased to about 500 togreater than 10,000 centistrokes, and a density in the range of fromabout 1.015 to about 1.060 g/cm3. More preferably they have a 100 degreeC. kinematic viscosity in the range 3,000 to 6,000 and density in therange 1.020 to 1.050 g/cm3.

[0026] Polyesters having the above-described properties are especiallyuseful as blood partitioning agents in blood collection vessels wherethey provide a continuous integral barrier or seal between the serum andclot portions of blood. In other words, the polyester completelypartitions the separated phases so that the serum and cellular or clotportions are no longer in contact at any point, forming a unitary sealwhich firmly adheres to the inner surface of the blood collectionvessel. By forming a continuous, integral barrier in this way, it ispossible to easily remove the serum or plasma portion by decanting orpipetting, with the clot portion remaining undisturbed in the collectionvessel.

[0027] The polyesters of this invention comprise the reaction product ofa polymeric fatty acid, resulting in the repeating “A” unit; adicarboxylic acid, resulting in the repeating “B” unit; a diol,resulting in the repeating “C” unit; and a moiety “D” having at leastone polymerizable carbon-carbon double bond and at least one functionalgroup capable of reacting with the ends of the polyester chain. Themolar ratio of the sum of the dicarboxylic acid member and the polymericfatty acid to the diol member is in the range from about 1:1.5 to about1:0.67

[0028] The “A” unit of the invention is the residue of a polymeric fattyacid, particularly preferred is the residue of C₃₆ dimer acid. Suitablepolymeric fatty acids have the formula:

HOOC—R_(A)—COOH

[0029] wherein R_(A) is an aliphatic or aromatic moiety having fromabout 20 to about 50 carbon atoms, preferably from about 22 to about 42carbon atoms. The polymeric fatty acids suitable for use in thepolyesters of the invention, are obtained by the polymerization ofolefinically unsaturated monocarboxylic acids having from 16 to 22carbon atoms, such as oleic acid, linolenic acid, linoleic acid,eleostearic acid and the like. Polymeric fatty acids and processes fortheir production are known to the art and by way of illustrationreference may be had to U.S. Pat. Nos. 2,793,219 and 2,955,121, theentire disclosures of which are herein incorporated by reference.Polymeric fatty acids useful for this invention preferably will have astheir principal component a C₃₆ dimer acid. C₃₆ dibasic acids areobtained by the dimerization of two moles of a C₁₈ unsaturatedmonocarboxylic acid such as oleic acid or linoleic acid or mixturesthereof (e.g., tall oil fatty acids). They typically contain 75% byweight or more C₃₆ dimer acid and have an acid value in the range180-215, saponification value in the range 190-215 and neutralequivalent from 265 to 310. The dimer acids may be hydrogenated prior touse. To increase the C₃₆ dimer content and reduce the amount ofby-product acids including unreacted mono-basic acid trimer and higherpolymer acids, the polymeric fatty acid can be molecularly distilled orotherwise fractionated. Especially useful polyester compositions areobtained using polymeric fatty acids having C₃₆ dibasic acid contents of85% by weight or more.

[0030] The “B” unit of the invention is the residue of a diacid. Diacidssuitable for use as the dicarboxylic acid member, component “B” of thepolyesters, include oxalic acid and dicarboxylic acids of the formula:

HOOC—R₁—COOH

[0031] where R₁ is a divalent alkylene chain having from 1 to 46 carbonatoms, and preferably is selected from the group consisting of divalentaliphatic chains of 1-34 carbon atoms and more preferably of from 3 to34 carbon atoms; divalent cycloaliphatic chains of 3-34 carbon atoms;arylene chains of from 6-34 carbon atoms, preferably of from 9-34;alkarylene chains of from 7-34 carbon atoms, and alkarylalkylene chainsof from 8-34 carbon atoms.

[0032] Suitable diacids useful in the practice of the present inventioninclude, but are not limited to malonic acid, succinic acid,methylmalonic acid, fumaric acid, maleic acid, acetylene dicarboxylicacid, glutaric acid, ethylmalonic acid, dimethylmalonic acid,methylsuccinic acid, citraconic acid, glutasconic acid, itaconic add,mesaconic acid, adipic acid, 2-dimethylsuccinic acid, 3-methylglutaricadd, hydromuconic acid, muconic add, pimelic acid, butylmalonic acid,diethylmalonic acid, 2-dimethylglutaric acid, 2-ethyl, 2-methylsuccinicacid, 3-methyladipic acid, cyclopentanedicarboxylic acid, suberic acid,cyclohexanedicarboxylic acid, isophthalic acid, terephthalic acid,azelaic acid, 5-norbomene-2,3-dicarboxylic acid, phenylmalonic acid,sebacic acid, camphoric acid, 1-cyclohexanediacetic acid,cyclohexylsuccinic acid, benzylmalonic acid, phenylene diacetic acid,phenylsuccinic acid, undecanedioic acid, 3-phenylglutaric acid,1,10-decanedicarboxylic acid, 4-phenylenedipropionic acid, naphthalenedicarboxylic acid, 1,11-undecanedicarboxylic acid,1,12-dodecanedicarboxylic acid, 4-biphenyidicarboxylic acid, diphenicacid, hexadecanedioic acid, octadecanedioic acid, octadecenedioic acid,dimer acids and mixtures thereof. Especially preferred are adipic,azelaic, sebacic, and dodecanedioic acids.

[0033] It will be apparent to those skilled in the art that the variousart-recognized equivalents of the aforementioned dicarboxylic acids,including lower alkylesters, anhydrides and acid chlorides thereof, maybe employed in preparing the polyesters of the invention. Accordingly,as used herein, the term “acid” is intended to encompass such acidderivatives. Methyl esters are particularly advantageous for thepreparation of the polyesters described herein. Mixtures of acids,anhydrides and esters may also be reacted to obtain the desired product.

[0034] The equivalents ratio of short-chain dibasic add (“B” componentof the polyester) to polymeric fatty acid (“A” component of thepolyester) will range from about 4:1 to 32:1 and more preferably will bein the range 5:1 to 19:1. An essentially stoichiometric amount of thedibasic acid mixture is reacted with the branched-chain diols(s) toobtain the polyesters.

[0035] The “C” unit in the polyester of the invention is the residue ofa diol. Suitable diols useful in the polyester of the invention compriseone or more esterifiable dihydric alcohol components of the formula:

HO—R_(C)—OH

[0036] wherein R_(C)=(CH_(n) R_(m))_(k) wherein n=0, 1 or 2; R=H, C₁ toC₁₀ alkyl, CH₂OCH₂CH₂, CH₂CH₂OCH₂CH₂OCH₂CH₂; m=0, 1, or 2; n+m=2; k=1 to10.

[0037] Preferred diols are branched-chain aliphatic dihydric alcoholshaving 3 to 8 carbon atoms. Mixtures of branched-chain diols are alsoadvantageously employed as are mixtures of a branched-chain andstraight-chain aliphatic saturated diols wherein the branched-chain diolconstitutes at least 50 percent by weight, and more preferably, greaterthan 70 percent by weight of the total diols present. When using amixture of branched-chain and straight-chain aliphatic saturated diols,the preferred molar ratio of the respective diols is from about 1:1 toabout 99:1, preferably from about 3.5:1 to about 99:1, and morepreferably from about 5:1 to about 99:1. The hydroxyl groups of the diolmay be either primary or secondary, however, diols having tertiaryhydroxyl groups are not recommended. For the purpose of this invention adiol containing a secondary hydroxyl group is considered to be abranched-chain diol. Useful branched-chain diols include, but are notlimited to, 2,2-dimethyl-1,3-propanediol (neopentyl glycol),2-methyl-1,3 -propanediol, 3-methyl-1,5-pentanediol,2,2,4-trimethyl-1,3-pentanediol, 3-methyl-2,3-pentanediol,1,2-propanediol, 1,3-butanediol, 1,2-butanediol, 1,2-pentanediol,1,3-pentanediol, 1,4-pentanediol and the like. Preferred diols for thisinvention contain from 3 to 5 carbon atoms and exceptional results areobtained using neopentyl glycol or a mixture of neopentyl glycol and1,2-propanediol. In one of the preferred embodiments of this inventionwhere a mixture of neopentyl glycol and 1,2-propanediol is used theequivalents ratio of the respective diols ranges from about 1:1 to about99:1, preferably from about 3.5:1 to about 99:1, and more preferablyfrom about 5:1 to about 99:1. Useful straight-chain (linear) aliphaticdiols can have from 2 to 8 carbon atoms and include, but are not limitedto, ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,6-hexanediol andthe like. Additional useful diols within the scope of the invention arediethylene glycol and triethylene glycol.

[0038] Additionally, a dimer diol which is a compound of the formula:

HO—R_(A)—OH

[0039] wherein R_(A) is defined as above is within the scope of usefuldiols for the present invention. These dimer diols are more fullydescribed in U.S. Pat. No. 5,101,009 which is incorporated herein byreference.

[0040] D=is a residue of a compound having at least one polymerizablecarbon-carbon double bond and at least one functional group capable ofreacting with the ends of the polyester chain. The D moiety can be theresidue of any ethylenically unsatuarated mono- or poly-functionalcompound capable of reacting with the ends of the polyester chain,examples of which include, but are not limited to, acrylic acid,methacrylic acid; acrylate or methacrylate esters such as methylacrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate,particularly preferred compounds are acrylic and methacrylic alkylesters wherein the alkyl group has from 1 to 4 carbon atoms;hydroxyalkyl acrylates and methacrylates of the following formula:

CH₂=CR²—C(O)O—R³—OH

[0041] wherein R is hydrogen or methyl and R is a linear or a branchedalkylene group having from 2 to 10 carbon atoms, preferably from 2 to 6carbon atoms, examples of which include but are not limited to,2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, 3-hydroxypropylacrylate, 2-hydroxybutyl acrylate, 4-hydroxybutyl acrylate,3-hydroxypentyl acrylate, 6-hydroxynonyl acrylate, 2-hydroxyethylmethacrylate, 2-hydroxypropyl methacrylate, 3-hydroxypropylmethacrylate, 2-hydroxybutyl methacrylate, 2-hydroxypentyl methacrylate,5-hydroxypentyl methacrylate, 7-hydroxyheptyl methacrylate and5-hydroxydecyl methacrylate; oligomers substituted with multipleacrylate ester groups mixed with low molecular weight monofunctional,difunctional, or trifunctional acrylate monomers, for example hexanedioldiacrylate; vinyl esters, such as vinyl acetate; ethylenicallyunsaturated mono-carboxylic acids and reactive derivatives thereof (addhalide (e.g., chloride), anhydride, ester, salt) examples of whichinclude, but are not limited to, alpha, beta-ethylenically unsaturatedcarboxylic acids containing from about 3 to about 8 carbon atoms;monovinyl esters of saturated and unsaturated aliphatic, monobasic andpolybasic acids, such as the vinyl esters of the following acids:propionic, isobutyric, caproic, oleic, stearic, acrylic, methacrylic,crotonic, succinic, maleic, fumaric, itaconic hexahydrobenzoic, citric,tartaric, etc., as well as the corresponding allyl, methallyl, etc.,esters of the aforementioned acids, the itaconic acid monoesters anddiesters, such as the methyl, ethyl, butyl esters, etc.; the maleic andfumaric acid monoesters.

[0042] Conventional esterification procedures and equipment are used toobtain the polyester of the invention. The reactive components arenormally added to the reaction vessel as a unit charge and the reactionmixture is then heated with agitation at a temperature from about 120degree to about 250 degree C. for a period of time sufficient tosubstantially complete the esterification reaction. The reaction may bedriven to completion by application of vacuum (typically 1-5 mm Hgabsolute at about 150 degree to about 250 degree C.) until the desiredproperties are obtained. Vacuum distillation removes the final traces ofwater, any excess reactants and small amounts of other volatilematerials present in the reaction mixture. Alternatively, all thereactive components except the moiety having at least one polymerizablecarbon-carbon double bond and at least one functional group capable ofreacting with the ends of the polyester chain can be added to thereaction vessel and heated until they are melted and form a homogeneousmixture at which point the moiety having at least one polymerizablecarbon-carbon double bond and at least one functional group capable ofreacting with the ends of the polyester chain can be added and thereaction carried out as described previously.

[0043] If improvement in color is desired, the polyester may be bleachedby any of the well known and accepted bleaching methods, e.g., usinghydrogen peroxide or chlorite. Alternatively, the polyester may bedecolorized by filtering through a filter aid, e.g., charcoal orbleaching clay.

[0044] The rate of esterification can be enhanced by the use of knownesterification catalysts. If a catalyst is used it is not necessary thatit be present throughout the entire reaction. It is sometimesadvantageous in order to obtain products having good color and low acidvalue, preferably less than 10, to add the catalyst during the finalstages of the reaction. At the same time the pressure can be reduced foreven better results. While the esterification can be carried outentirely at atmospheric pressure it is most desirable to reduce thepressure, typically to about 1-50 mm Hg. at about 150 degree to about250 degree C., during the latter stages to facilitate removal of thefinal traces of water and excess glycol which may be present and toreduce the acid value to the desired level. Suitable esterificationcatalysts for enhancing the rate of esterification of free carboxylgroups include phosphoric acid, sulfuric acid, toluenesulfonic acid,methane sulfonic add, sodium carbonate and the like. The amount of suchcatalyst may vary widely, but most often will be in an amount from about0.1% to about 0.5% by weight, based on the total reactant charge.Catalysts useful for effecting ester interchange include dibutyltindiacetate, stannous oxalate, alkyl tin oxides, such as dibutyltin oxide;tetrabutyl titanate, zinc acetate and the like. These catalysts aregenerally employed in an amount ranging from about 0.01% to 0.05% byweight, based on the total resistant charge. When such catalysts areused, it is not necessary that they be present throughout the entirereaction. It is sometimes advantageous in order to obtain productshaving good color and relatively low acid value, on the order of 2 mgKOH/gm, or less, to add the catalyst during the final stages of thereaction. Upon completion of the reaction, the catalyst may bedeactivated and removed by filtration or other conventional means.

[0045] Reaction solvents, such as benzene, toluene, xylene and the likemay be employed for the reaction. However, the use of reaction solventsis not necessary. It is generally considered desirable to conduct thereaction without solvents since the resultant polyester can be directlyused as it is obtained from the reaction vessel. A small excess (basedon the equivalents of acid present) of a volatile diol component may beused if desired. The excess diol serves as the reaction medium andreduces the viscosity of the reaction mixture. The excess diol isdistilled off as the esterification is carried to completion and may berecycled to the reactor, if desired. Generally, about 20% by weightexcess volatile diol will suffice. The preferred volatile diol is1,2-propanediol. It will be evident to one skilled in the art that, ifthe esterification is carried out in a continuous or semi-continuousmanner, it will be necessary to replenish the reactants as they areconsumed. Multiple vessel arrangements can be used for continuousproduction of these polyesters.

[0046] The polyesters of this invention can optionally be made intoblood partitioning compositions by formulating with up to about 35weight percent of an inert filler. These fillers can be added to thepolyester to increase the density of the polyester composition since allof the commonly used fillers have densities greater than that of thepolyester. The fillers also impart thixotropic properties to the barriercompositions. Polyesters containing small amounts of inert fillers,particularly silica, exhibit improved flow characteristics duringcentrifuging so that the compositions more readily located at theinterface between the light and heavy phases. When centrifuging isterminated, however, the compositions return to their original state andform a highly viscous, continuous and integral barrier between the clotand serum portions. The inert fillers used are in a finely powderedstate and preferably constitute from about 0.5 to 25 weight percent ofthe total composition. While silica, including the various amorphousform of silica, such as precipitated silica and fumed silica, and thehydrophobic silicas treated with silanes or polysiloxanes, areparticularly useful with the polyesters of this invention, other inertmaterials such as alumina, talc and other silicates, bentonite and othernaturally occurring montmorillonite-rich mineral clays can also beemployed.

[0047] Preparation of blood partitioning compositions using thepolyesters of the invention may be carried out in the manner describedin commonly owned U.S. Pat. Nos. 4,101,422 and 4,148,764, the entiredisclosures of which are incorporated by reference in the presentspecification, as if set forth herein in full.

[0048] The present invention also pertains to a method of partitioningblood comprising the steps of

[0049] (i) placing an effective amount of the polyester of the inventiondescribed above into a blood collecting tube;

[0050] (ii) curing the polyester of the invention;

[0051] (iii) introducing the blood to be partitioned into the tube, and

[0052] (iv) effecting the partitioning of the said blood through theaction of centrifugal force.

[0053] One method by which the new compositions of this invention can becured or converted to the infusible state, alone or in admixture withother monomers or polymers is by exposure to radiation alone or in thepresence of radical generating catalysts such as benzoin, benzoinethers, and Michler's Ketone. The free radical initiator is typicallypresent at from about 0.01 to about 20% by weight of thepolymerizable/curable components. Examples of useful radiation includeultraviolet light and ionizing radiation such as generated by X-Raymachines; electron accelerators such as van der Graaf machines,travelling wave linear accelerators, particularly of the type describedin U.S. Pat. No. 2,736,609, natural and synthetic radioactive material,for example cobalt 60, etc. To ensure that the composition does notprematurely polymerize, a free radical inhibitor may be added to thepolymerizable composition. Examples of suitable inhibitors includehydroquinone and the methyl ether thereof or butylated hydroxy tolueneat a level of from about 5 ppm to about 2000 ppm by weight of thepolymerizable components. Additives which are particularly useful inprolonging the shelf-life of the composition can also be used, e.g.,ultra-violet stabilizers such as FLORSTAB® UV-II from Kromachem.

[0054] In the method of partitioning blood, according to the invention,the composition, optionally containing a photoinitiator, is placed in ablood collection tube and subsequently exposed to a radiation sourceuntil the desired viscosity is obtained. Sources of radiant energyappropriate for initiating cure of the formulations have been describedextensively in the literature and are well known to those skilled in theart. These include various sources of particulate and non-particulateradiation producing wavelengths generally less than 700 nanometers.Especially useful is actinic radiation in the 180-440 nm range which canbe conveniently obtained by use of one of several commercially availableultra-violet sources specifically intended for this purpose. Theseinclude low, medium and high pressure mercury vapor lamps, He—Cd and Arlasers, xenon arc lamps, etc. Photoinitiator systems having acorresponding sensitivity to light in this wave band can be incorporatedinto the formulation and upon irradiation lead to the formation ofreactive species capable of initiating free radical polymerization.Similarly, free radical polymerization may be induced by exposure of theformulation to an electron beam without the use of a photoinitiator.Equipment capable of generating a curtain of electrons with energiesbetween 150 and 300 KeV is particularly suitable for this purpose andits use is well documented in the literature.

[0055] Particularly preferred sources of radiation emit electromagneticradiation predominantly in the ultra-violet band. When such a source isused, the polymerizable composition preferably contains a photoinitiatorsusceptible to ultra-violet radiation, e.g., benzoin, benzoin ethers,alpha, alpha-dimethoxy-alpha-phenylacetophenone, diethoxyacetophenone,alpha-hydroxy-alpha, alpha-dimethylacetophenone, and1-benzoylcyclohexanol.

[0056] The amount of radiation necessary to cure the composition will ofcourse depend on the angle of exposure to the radiation, the quantity ofcomposition placed in the collection tube, and the amount ofpolymerizable groups in the partitioning composition, as well as thepresence or absence of a free radical initiating catalyst. For any givencomposition, experimentation to determine the amount of radiationsensitive pi bonds not cured following exposure to the radiation sourceis the best method of determining the amount and duration of theradiation required. Typically, an ultra-violet source with a wavelengthbetween 200 and 420 nm (e.g., a filtered mercury arc lamp) is directedat a measured quantity of partitioning composition carried on a conveyorsystem which provides a rate of passage past the ultra-violet sourceappropriate for the radiation absorption profile of the composition(which profile is influenced by the degree of cure desired, theeffective quantity of partitioning composition to be cured, and the rateof polymerization of the composition).

[0057] Determination of the extent of interaction between the polyestersof the invention and commonly monitored drugs may be carried out usingwell known recovery experiments and drug measurement techniques, suchas, gas chromatography, gas-liquid chromatography, high-performanceliquid chromatography, thin layer chromatography or immunoassaytechniques, including radioimmunoassay, enzyme immunoassay, fluorescencepolarization immunoassay, nephelometric assay, and the like. A varietyof suitable procedures are reported in the literature. See, for example,Bergqvist, et al., supra. Such determinations may be carried out usinghuman serum, or commercially available bovine serum, if desired.

[0058] The following examples are presented to illustrate the inventionmore fully, and are not intended, nor are they to be construed, as alimitation of the scope of the invention. In the examples, allpercentages are on a weight basis unless otherwise indicated.

EXAMPLES Example 1

[0059] The reaction was carried out in a four-necked, round-bottom flaskequipped with a stirrer, thermo watch, thermometer, nitrogen sweep and amedium length Vigreaux column fitted with a condenser, distillation headwith thermometer and receiver. The condenser was arranged so that waterand/or excess diol could be distilled from the reaction mixture ateither atmospheric or reduced pressure. The reactant charge was asfollows: Azelaic Acid 640.5 g C36 Dimer Acid* 324 g Neopentyl Glycol 420g 1,2-Propanediol 34.5 g

[0060] The acid value was measured as 295. The flask was heated untilall material was melted and appeared homogeneous. An additional chargeof: Acrylic acid 81 g

[0061] was then added to the flask. The temperature of the reactionmixture was brought to about 130 to 150 degree C. while maintaining thevapor temperature at about 100 degree - 120 degree C. and removing waterof reaction and was heated with the vapor coming off being heated andcondensed. The distillation continued until it was determined that thevapor coming from the reaction mixture was acrylic acid. The finalweight was 1346 g of material. The acid value was measured at 47.8,viscosity at 100C was 139.1 centistrokes and the density at 25C wasmeasured as 1.0201.

Example 2

[0062] 30 ml of the material made in example 1 was exposed to UV light:Hours of exposure Viscosity at 100C 6-8 254 12 426 16 755 20 4416 

Example 3

[0063] 30 ml of the material made in example 1 was exposed to 7 hours oflong wave UV light. The viscosity was measure at 312 and the density wasmeasured at 1.0216.

Example 4

[0064] The viscosity and density of a sample of unexposed materialproduced in example 1 was checked 12 days after it was made. Theviscosity was 143 and the density was 1.0206.

What is claimed is:
 1. A polyester comprising the repeating units A, B, C and moiety D wherein: A=(—C:O—R_(A)—O:C—) wherein A is a residue of a polymeric fatty acid and R_(A) is an aliphatic or aromatic moiety having from about 20 to about 50 carbon atoms; B=(—C:O—R_(B)—O:C—), wherein R_(B) is a member selected from the group consisting of a divalent aliphatic chain of 1-34 carbon atoms; a divalent cycloaliphatic chain of 3-34 carbon atoms; a divalent arylene chain of from 6-34 carbon atoms, a divalent alkarylene chain of from 7-34 carbon atoms, a divalent alkarylalkylene chain of from 8-34 carbon atoms and mixtures thereof; C=(—O—R_(C)—O—), wherein R_(C) is a member selected from the group consisting of compounds of the formula: R_(C)=(CH_(n) R_(m))_(k), wherein n=0, 1,2, or 3; R=H, C₁ to C₁₀ alkyl, CH₂0CH₂CH₂, CH₂CH₂OCH₂CH₂O CH₂CH₂; m=0, 1, or 2; n+m=2; k=1 to 10; and D is a residue of a compound having at least one polymerizable carbon-carbon double bond and at least one functional group capable of reacting with the ends of the polyester chain.
 2. The polyester of claim 1 wherein the polyester has a density at room temperature in the range of about 1.01 to about 1.09.
 3. The polyester of claim 1 wherein the polyester has a kinematic viscosity of between about 100 to about 1000 centistokes at 100 degree C.
 4. The polyester of claim 1 wherein the polyester has a kinematic viscosity of between about 3000 to about 6000 centistokes at 100 degree C after curing.
 5. The polyester of claim 1 wherein, R_(B) is a residue of azelaic acid, R_(C) is the residue of neopentyl glycol and 1,2 propanediol.
 6. The polyester of claim 1 wherein the molar ratio of the sum of R_(A) and R_(B) to R_(C) is in the range from about 1:1.5 to about 1:0.67.
 7. The polyester of claim 5 wherein the molar ratio of R_(A) to R_(B) is in the range from about 1:4 to 1:32.
 8. The polyester of claim 1 wherein the molar ratio of the sum of R_(A) and R_(B) to R_(C) is in the range from about 1:1.5 to about 1:0.67, wherein said Rc member is comprised of the residue of a first dihydric alcohol component and the residue of a second dihydric alcohol component wherein the first dihydric component is a branched-chain aliphatic saturated diol and the second dihydric component is a straight-chain aliphatic saturated diol, wherein the branched-chain diol constitutes at least 50 percent by weight of the total diols present.
 9. The polyester of claim 8 wherein the polyester has a density at room temperature in the range of from about 1.01 to about 1.09.
 10. The polyester of claim 8 wherein the polyester has a kinematic viscosity of between about 100 to about 1000 centistokes at 100 degree C.
 11. The polyester of claim 8 wherein the B unit is the residue of azelaic acid, the first dihydric alcohol component is neopentyl diol and the second dihydric alcohol component is propylene glycol.
 12. The polyester of claim 8 wherein the molar ratio of the first dihydric alcohol component and the second dihydric alcohol component is from about 5:1 to about 99:1.
 13. The polyester of claim 8 wherein the polyester is cured using a source of radiation.
 14. The polyester of claim 13 wherein the polyester has a kinematic viscosity of between about 1000 to about 6000 centistokes at 100 degree C after curing.
 15. The polyester of claim 13 wherein the source of radiation is selected from the group consisting of ultraviolet light, ionizing radiation; electron accelerators, natural and synthetic radioactive material and combinations thereof.
 16. A method of partitioning blood comprising the steps of: (i) placing an effective amount of a polyester comprising the repeating units A, B, C and moiety D wherein: A=(—C:O—R_(A)—O:C—) wherein A is the residue of a polymeric fatty acid and R_(A) is an aliphatic or aromatic moiety having from about 20 to about 50 carbon atoms; B=(—C:O—R_(B)—O:C—), wherein R_(B) is a member selected from the group consisting of a divalent aliphatic chain of 1-34 carbon atoms; a divalent cycloaliphatic chain of 3-34 carbon atoms; a divalent arylene chain of from 6-34 carbon atoms, a divalent alkarylene chain of from 7-34 carbon atoms, a divalent alkarylalkylene chain of from 7-34 carbon atoms and mixtures thereof; C=(—O—R_(C)—O—), wherein R_(C) is a member selected from the group consisting of compounds of the formula: R_(C)=(CH_(n) R_(m))_(k), wherein n=0, 1,2, or 3; R=H, C, to C₁₀ alkyl, CH₂OCH₂CH₂, CH₂CH₂OCH₂CH₂OCH₂CH₂; m=0, 1, or 2; n+m= 2; k=1 to 10; and D is the residue of a compound having at least one polymerizable carbon-carbon double bond and at least one functional group capable of reacting with the ends of the polyester chain; into a blood collecting tube; (ii) curing the polyester; (iii) introducing the blood to be partitioned; and (iv) effecting the partitioning of the blood through the action of centrifugal force.
 17. The method of claim 16 wherein R_(B) is a divalent aliphatic chain containing 3 to 34 carbon atoms.
 18. The method of claim 16 wherein R_(B) is a member selected from the group consisting of a divalent aliphatic chain of 3-34 carbon atoms, and said polyester exhibits a room temperature density in the range of from about 1.01 to about 1.09, a kinematic viscosity of from about 100 centistokes to about 1000 centistokes at 100 degree C. prior to the curing step (ii).
 19. The method of claim 16 wherein R_(C) is the residue of a mixture of neopentyl glycol and 1,2 propanediol.
 20. The method of claim 16 wherein R_(B) is a residue of azelaic acid, R_(C) is the residue of a mixture of neopentyl glycol and 1,2 propanediol.
 21. The method of claim 16 wherein the molar ratio of the sum of R_(A) and R_(B) to R_(C) is in the range from about 1:1.5 to about 1:0.67.
 22. The method of claim 16 wherein the molar ratio of the sum of R_(A) and R_(B) to R_(C) is in the range from about 1:1.5 to about 1:0.67, wherein said R_(C) member is comprised of the residue of a first dihydric alcohol component and the residue of a second dihydric alcohol component wherein the first dihydric component is a branched-chain aliphatic saturated diol and the second dihydric component is a straight-chain aliphatic saturated diol, wherein the branched-chain diol constitutes at least 50 percent by weight of the total diols present.
 23. The method of claim 22 wherein the molar ratio of the first dihydric alcohol component and the second dihydric alcohol component is from about 5:1 to about 99:1.
 24. The method of claim 16 wherein the polyester is cured using a source of radiation.
 25. The method of claim 24 wherein the polyester has a kinematic viscosity of between about 1000 to about 6000 centistokes at 100 degree C after the curing step.
 26. The method of claim 24 wherein the source of radiation is selected from the group consisting of ultraviolet light, ionizing radiation; electron accelerators, natural and synthetic radioactive material and combinations thereof.
 27. The method of claim 16 wherein the polyester comprises about one mole of a dicarboxylic acid member and one mole of a diol member wherein said acid member is comprised of a first dicarboxylic acid component having 36 carbon atoms, and a second dicarboxylic acid component is selected from the group consisting of compounds with two carboxylic acids moieties linked by an aliphatic chain of 1-34 carbon atoms, a cycloaliphatic chain of 3-34 carbon atoms, an arylene chain of from 6-34 carbon atoms, an alkarylene chain of from 7-34 carbon atoms, and an alkarylalkylene chain of from 8-34 carbon atoms, or mixtures thereof; and wherein said diol member is comprised of a first dihydric alcohol component and a second dihydric alcohol component, each dihydric alcohol component being independently selected from compounds having the formula C=the group (—O—R_(C)—O—) from a dihydric alcohol wherein R_(C) is a member selected from the group consisting of compounds of the formula: R_(C)=(CH_(n) R_(m))_(k) wherein n=0, 1,2, or 3; R=H, C₁ to C₁₀ alkyl, CH₂OCH₂CH₂, CH₂CH₂OCH₂CH₂OCH₂CH₂; m=0, 1, or 2; n+m=2; k=1 to
 10. 28. The method of claim 27 wherein the second dicarboxylic acid member is azelaic acid, the first dihydric alcohol is neopentyl glycol and the second dihydric alcohol component is 1,2 propanediol.
 29. The method of claim 27 wherein in the polyester the molar ratio of the dicarboxylic acid member to the diol member is in the range from about 1:1.5 to about 1:0.67.
 30. The method of claim 27 wherein in the polyester the molar ratio of the first dihydric alcohol component to the second dihydric alcohol component is in the range of from about 5:1 to about 99:1.
 31. The method of claim 27 wherein in the polyester the molar ratio of the first dicarboxylic acid component to the second dicarboxylic acid component is in the range of from about 1:4 to about 1:32.
 32. The method of claim 27 wherein the polyester is cured using a source of radiation.
 33. The method of claim 27 wherein the polyester has a kinematic viscosity of between about 1000 to about 6000 centistokes at 100 degree C after curing.
 34. The method of claim 27 wherein the source of radiation is selected from the group consisting of ultraviolet light, ionizing radiation, electron accelerators, natural and synthetic radioactive material and combinations thereof.
 35. A process comprising the steps of: A) combining: 1) a polymeric fatty acid; 2) a short chain diacid selected from the group consisting of oxalic acid, diacids of the general formula: HOOC—R_(B)—COOH wherein: R_(B) is a member selected from the group consisting of a divalent aliphatic chain of 1-34 carbon atoms; a divalent cycloaliphatic chain of 3-34 carbon atoms; a divalent arylene chain of from 6-34 carbon atoms, a divalent alkarylene chain of from 7-34 carbon atoms, a divalent alkarylalkylene chain of from 8-34 carbon atoms and mixtures thereof; 3) a diol of the general formula: HO—R_(C)—OH, wherein R_(C) is a member selected from the group consisting of compounds of the formula: R_(C)=(CH_(n) R_(m))_(k), wherein n=0, 1,2, or 3; R=H, C, to C₁₀ alkyl, CH₂OCH₂CH₂, CH₂CH₂OCH₂CH₂OCH₂CH₂; m=0, 1, or 2; n+m=2; k=1 to 10; and 4) a compound having at least one polymerizable carbon-carbon double bond and at least one functional group capable of reacting with the ends of the polyester chain; and B) carrying out an esterification reaction.
 36. The process of claim 35 wherein the polyester has a density at room temperature in the range of about 1.01 to about 1.09.
 37. The process of claim 35 wherein the polyester has a kinematic viscosity of between about 100 to about 1000 centistokes at 100 degree C.
 38. The process of claim 35 wherein the polyester has a kinematic viscosity of between about 3000 to about 6000 centistokes at 100 degree C after curing.
 39. The process of claim 35 wherein, R_(B) is a residue of azelaic acid, R_(C) is the residue of neopentyl glycol and 1,2 propanediol.
 40. The process of claim 35 wherein the molar ratio of the sum of polymeric fatty acid and R_(B) to R_(C) is in the range from about 1:1.5 to about 1:0.67.
 41. The process of claim 35 wherein the molar ratio of the polymeric fatty acid to R_(B) is in the range from about 1:4 to 1:32.
 42. The product of the process of claim 35 .
 43. The process of claim 35 wherein the molar ratio of the sum of the polymeric fatty acid and R_(B) to R_(C) is in the range from about 1:1.5 to about 1:0.67, wherein said Rc member is comprised of the residue of a first dihydric alcohol component and the residue of a second dihydric alcohol component wherein the first dihydric component is a branched-chain aliphatic saturated diol and the second dihydric component is a straight-chain aliphatic saturated diol, wherein the branched-chain diol constitutes at least 50 percent by weight of the total diols present.
 44. The process of claim 43 wherein the B unit is the residue of azelaic acid, the first dihydric alcohol component is neopentyl diol and the second dihydric alcohol component is propylene glycol.
 45. The process of claim 43 wherein the molar ratio of the first dihydric alcohol component and the second dihydric alcohol component is from about 5:1 to about 99:1.
 46. The process of claim 35 wherein the polyester is cured using a source of radiation.
 47. The process of claim 46 wherein the source of radiation is selected from the group consisting of ultraviolet light, ionizing radiation, electron accelerators, natural and synthetic radioactive material and combinations thereof. 